title: Interleukin-17A: a unique pathway in immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis.
abstract: Experimental evidence points to the importance of the cytokine interleukin-17A (IL-17A) in the pathogenesis of several immunoinflammatory diseases including psoriasis, psoriatic arthritis and rheumatoid arthritis. Although a principal effector of T helper type 17 cells, IL-17A is produced by many other cell types including CD8(+) T cells and γδ T cells, and is found at high levels associated with mast cells and neutrophils at sites of skin and joint disease in humans. IL-17A up-regulates expression of numerous inflammation-related genes in target cells such as keratinocytes and fibroblasts, leading to increased production of chemokines, cytokines, antimicrobial peptides and other mediators that contribute to clinical disease features. Importantly, IL-17A must be considered within the context of the local microenvironment, because it acts synergistically or additively with other pro-inflammatory cytokines, including tumour necrosis factor. Several direct IL-17A inhibitors have shown promising activity in proof of concept and phase 2 clinical studies, thereby providing confirmation of experimental data supporting IL-17A in disease pathogenesis, although levels of response are not predicted by pre-clinical findings. IL-17A inhibitors produced rapid down-regulation of the psoriasis gene signature and high clinical response rates in patients with moderate-to-severe plaque psoriasis, consistent with an important role for IL-17A in psoriasis pathogenesis. Clinical response rates with IL-17A inhibitors in psoriatic arthritis and rheumatoid arthritis, however, were improved to a lesser degree compared with placebo, suggesting that IL-17A is either important in a subset of patients or plays a relatively minor role in inflammatory joint disease. Ongoing phase 3 clinical trials should provide further information on the role of IL-17A in these diseases.
authors.affiliation: Department of Rheumatology, Guy's & St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Kirkham
authors.forename: Arthur
authors.initials: A
authors.lastname: Kavanaugh
authors.forename: Kristian
authors.initials: K
authors.lastname: Reich
mesh_terms: D000818:Animals; D015535:Arthritis, Psoriatic / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology; D002986:Clinical Trials as Topic; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000502:physiology*; D011565:Psoriasis / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology; D053722:Receptors, Interleukin-17 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D020381:Interleukin-17; D053722:Receptors, Interleukin-17
keywords: biological therapy; interleukin-17A; psoriasis; psoriatic arthritis; rheumatoid arthritis